Vitamin D receptor defects: the story of hereditary resistance to vitamin D

Vitamin D, synthesized in the epidermis in response to UV radiation, is devoid of any biological activity. The hormonal activity is due to its metabolite, 1 alpha, 25-dihydroxyvitamin D, named calcitriol. The actions of calcitriol are mediated by the vitamin D receptor, VDR, a member of the nuclear receptor family. The clinical presentation of hypocalcaemia, secondary hyperparathyroidism, early onset rickets in the presence of normal levels of serum 25-hydroxyvitamin D and markedly elevated serum levels of calcitriol is indicative of hereditary vitamin D resistant rickets, HVDRR. HVDRR is a recessive autosomal disorder that has been described in approximately 60 unrelated families. Dermal fibroblasts and peripheral blood lymphocytes can serve as target organ models to evaluate the interaction of calcitriol and its effector system. Failure of calcitriol to induce the enzyme 25-hydroxyvitamin D3 24 hydroxylase in fibroblasts or to inhibit lymphocyte mitogenesis can serve as the diagnosis for HVDRR Transfection studies employing site directed mutagenesis to mimic the natural mutations in VDR, have identified mutations that interfere with the major events in VDR signaling: hormone binding; heterodimerization with RXR; binding to vitamin D response elements in the promoters of target genes; and interaction with co- activators. Interference with one or more of these steps results in the clinical syndrome of HVDRR.